Browsing by Author "DuVall, Scott L."

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    A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation
    (Springer Nature, 2022) Vujkovic, Marijana; Ramdas, Shweta; Lorenz, Kim M.; Guo, Xiuqing; Darlay, Rebecca; Cordell, Heather J.; He, Jing; Gindin, Yevgeniy; Chung, Chuhan; Myers, Robert P.; Schneider, Carolin V.; Park, Joseph; Lee, Kyung Min; Serper, Marina; Carr, Rotonya M.; Kaplan, David E.; Haas, Mary E.; MacLean, Matthew T.; Witschey, Walter R.; Zhu, Xiang; Tcheandjieu, Catherine; Kember, Rachel L.; Kranzler, Henry R.; Verma, Anurag; Giri, Ayush; Klarin, Derek M.; Sun, Yan V.; Huang, Jie; Huffman, Jennifer E.; Townsend Creasy, Kate; Hand, Nicholas J.; Liu, Ching-Ti; Long, Michelle T.; Yao, Jie; Budoff, Matthew; Tan, Jingyi; Li, Xiaohui; Lin, Henry J.; Chen, Yii-Der Ida; Taylor, Kent D.; Chang, Ruey-Kang; Krauss, Ronald M.; Vilarinho, Silvia; Brancale, Joseph; Nielsen, Jonas B.; Locke, Adam E.; Jones, Marcus B.; Verweij, Niek; Baras, Aris; Reddy, K. Rajender; Neuschwander-Tetri, Brent A.; Schwimmer, Jeffrey B.; Sanyal, Arun J.; Chalasani, Naga; Ryan, Kathleen A.; Mitchell, Braxton D.; Gill, Dipender; Wells, Andrew D.; Manduchi, Elisabetta; Saiman, Yedidya; Mahmud, Nadim; Miller, Donald R.; Reaven, Peter D.; Phillips, Lawrence S.; Muralidhar, Sumitra; DuVall, Scott L.; Lee, Jennifer S.; Assimes, Themistocles L.; Pyarajan, Saiju; Cho, Kelly; Edwards, Todd L.; Damrauer, Scott M.; Wilson, Peter W.; Gaziano, J. Michael; O'Donnell, Christopher J.; Khera, Amit V.; Grant, Struan F. A.; Brown, Christopher D.; Tsao, Philip S.; Saleheen, Danish; Lotta, Luca A.; Bastarache, Lisa; Anstee, Quentin M.; Daly, Ann K.; Meigs, James B.; Rotter, Jerome I.; Lynch, Julie A.; Regeneron Genetics Center; Geisinger-Regeneron DiscovEHR Collaboration; EPoS Consortium; VA Million Veteran Program; Rader, Daniel J.; Voight, Benjamin F.; Chang, Kyong-Mi; Medicine, School of Medicine
    Nonalcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease. Using a proxy NAFLD definition of chronic elevation of alanine aminotransferase (cALT) levels without other liver diseases, we performed a multiancestry genome-wide association study (GWAS) in the Million Veteran Program (MVP) including 90,408 cALT cases and 128,187 controls. Seventy-seven loci exceeded genome-wide significance, including 25 without prior NAFLD or alanine aminotransferase associations, with one additional locus identified in European American-only and two in African American-only analyses (P < 5 × 10-8). External replication in histology-defined NAFLD cohorts (7,397 cases and 56,785 controls) or radiologic imaging cohorts (n = 44,289) replicated 17 single-nucleotide polymorphisms (SNPs) (P < 6.5 × 10-4), of which 9 were new (TRIB1, PPARG, MTTP, SERPINA1, FTO, IL1RN, COBLL1, APOH and IFI30). Pleiotropy analysis showed that 61 of 77 multiancestry and all 17 replicated SNPs were jointly associated with metabolic and/or inflammatory traits, revealing a complex model of genetic architecture. Our approach integrating cALT, histology and imaging reveals new insights into genetic liability to NAFLD.
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    Clinical and genetic risk factors for progressive fibrosis in metabolic dysfunction-associated steatotic liver disease
    (Wolters Kluwer, 2024-07-05) Kaplan, David E.; Teerlink, Craig C.; Schwantes-An, Tae-Hwi; Norden-Krichmar, Trina M.; DuVall, Scott L.; Morgan, Timothy R.; Tsao, Philip S.; Voight, Benjamin F.; Lynch, Julie A.; Vujković, Marijana; Chang, Kyong-Mi; Medical and Molecular Genetics, School of Medicine
    Background: Fibrosis-4 (FIB4) is a recommended noninvasive test to assess hepatic fibrosis among patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we used FIB4 trajectory over time (ie, "slope" of FIB4) as a surrogate marker of liver fibrosis progression and examined if FIB4 slope is associated with clinical and genetic factors among individuals with clinically defined MASLD within the Million Veteran Program Cohort. Methods: In this retrospective cohort study, FIB4 slopes were estimated through linear regression for participants with clinically defined MASLD and FIB4 <2.67 at baseline. FIB4 slope was correlated with demographic parameters and clinical outcomes using logistic regression and Cox proportional hazard models. FIB4 slope as a quantitative phenotype was used in a genome-wide association analysis in ancestry-specific analysis and multiancestry meta-analysis using METAL. Results: FIB4 slopes, generated from 98,361 subjects with MASLD (16,045 African, 74,320 European, and 7996 Hispanic), showed significant associations with sex, ancestry, and cardiometabolic risk factors (p < 0.05). FIB4 slopes also correlated strongly with hepatic outcomes and were independently associated with time to cirrhosis. Five genetic loci showed genome-wide significant associations (p < 5 × 10-8) with FIB4 slope among European ancestry subjects, including 2 known (PNPLA3 and TM6SF2) and 3 novel loci (TERT 5.1 × 10-11; LINC01088, 3.9 × 10-8; and MRC1, 2.9 × 10-9). Conclusions: Linear trajectories of FIB4 correlated significantly with time to progression to cirrhosis, with liver-related outcomes among individuals with MASLD and with known and novel genetic loci. FIB4 slope may be useful as a surrogate measure of fibrosis progression.